The proposed research is to test aspects of the hypothesis of a relation between low specific activities of the enzyme lipoamide dehydrogenase and some cases of the recessive neurological syndrome, Friedreich's ataxia. The syndrome has been considered of unknown cause and untreatable. We will substantiate evidence that some cases are associated with low specific activities of the enzyme in homogenized platelets, that some of these cases have kinetic or heat-inactivation abnormalities suggestive of a structural mutation and that carriers can be detected and preclinical diagnoses made by assays and kinetic studies of the platelet enzyme. After the development of techniques to partially-purify the enzyme so as to free it from multi-molecular complexes and to identify its activity in electrophoresis--gels, we will determine: a) whether or not the human defects affect all the supposed isoenzymes of lipomide dehydrogenase, and b) the extent to which abnormalities in the platelet enzyme reflect changes in the enzyme in the brain. Future work will clarify whether the kinetic changes are due to abnormalities of the enzyme protein or of some modifying protein in the multi-molecular complexes. The research will provide: a) knowledge about the enzyme and about Friedreich's ataxia, b) a basis for future studies of pathophysiological mechanisms and metabolic approaches to treatment, and, potentially, c) a basis for precise biochemical methods for diagnosis, preclinical diagnosis and the detection of carriers of the lipoamide dehydrogenase deficiency form of Friedreich's ataxia.